Combination therapies for the treatment of cancer

Abstract

The present invention provides methods and compositions for treating cancer by administering an EP4 antagonist in combination with radiation therapy, antibody therapy and/or anti-metabolite chemotherapy.

1 . A method of treating cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with radiation therapy. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein said treating comprises an abscopal effect. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the EP4 antagonist is a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 one of R 1a  and R 1b  is hydrogen, and the other is methyl; or R 1a  and R 1b  are taken together to form a cyclopropyl ring; 
 R 2  is methyl or fluoromethyl; 
 R 3  is methyl; 
 R 4  is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy; 
 R 5  is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy; 
 R 6  is hydrogen, halo, methyl, or methoxy; 
 R 7  is hydrogen, halo, methyl, or methoxy; and 
 X is oxygen; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 6 , wherein said compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 6 , wherein said compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: breast cancers, cervical cancers, colorectal cancers, endometrial cancers, glioblastomas, head and neck cancers, kidney cancers, liver cancers, lung cancers, medulloblastomas, ovarian cancers, pancreatic cancers prostate cancers, skin cancers (e.g., melanoma) and urinary tract cancers. 
     
     
         10 . The method of  claim 1 , wherein the cancer is metastatic cancer. 
     
     
         11 . A method of generating a memory immune response against a cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with radiation therapy. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein said generating the memory immune response comprises an abscopal effect. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The method of  claim 11 , wherein the EP4 antagonist is a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 one of R 1a  and R 1b  is hydrogen, and the other is methyl; or R 1a  and R 1b  are taken together to form a cyclopropyl ring; 
 R 2  is methyl or fluoromethyl; 
 R 3  is methyl; 
 R 4  is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy; 
 R 5  is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy; 
 R 6  is hydrogen, halo, methyl, or methoxy; 
 R 7  is hydrogen, halo, methyl, or methoxy; and 
 X is oxygen; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein said compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 16 , wherein said compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 11 , wherein the cancer is selected from the group consisting of breast cancers, cervical cancers, colorectal cancers, endometrial cancers, glioblastomas, head and neck cancers, kidney cancers, liver cancers, lung cancers, medulloblastomas, ovarian cancers, pancreatic cancers prostate cancers, skin cancers (e.g., melanoma) and urinary tract cancers. 
     
     
         20 . The method of  claim 11 , wherein the cancer is metastatic cancer. 
     
     
         21 . The method of  claim 11 , wherein the memory immune response comprises epitope spreading. 
     
     
         22 . The method of  claim 1 , wherein the method further comprises administering an anti-metabolite chemotherapy in combination with the EP4 antagonist and radiation therapy. 
     
     
         23 . The method of  claim 22 , wherein the anti-metabolite is a deoxynucleoside analog. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 23 , wherein the deoxynucleoside analog is capecitabine. 
     
     
         26 . A method of treating cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with an anti-metabolite chemotherapy. 
     
     
         27 . The method of  claim 26 , wherein the anti-metabolite is a deoxynucleoside analog. 
     
     
         28 - 29 . (canceled)